Autoimmune diseases arise from an overactive immune response of the immune system against substances and tissues normally present in a multicellular organism, i.e. the immune system attacks its own components. This may be restricted to certain organs or involve a particular tissue in different places. The treatment of autoimmune diseases is typically with immunosuppression—medication which decreases the whole immune response.
Lupus is an autoimmune disease that is estimated to affect nearly 1.4 million Americans, primarily women between the ages of 20-40. Lupus involves antibodies that attack connective tissue. The principal form of lupus is a systemic one (systemic lupus erythematosus; SLE). SLE is a chronic autoimmune disease with strong genetic as well as environmental components (See, e.g., Hochberg M C, Dubois' Lupus Erythematosus. 5th ed., Wallace D J, Hahn B H, eds. Baltimore: Williams and Wilkins (1997); Wakeland E K, et al., Immunity 2001; 15(3):397-408; Nath S K, et al., Curr. Opin. Immunol. 2004; 16(6):794-800; D'Cruz et al., Lancet (2007), 369:587-596). Various additional forms of lupus are known, including, but not limited to, cutaneous lupus erythematosus (CLE), lupus nephritis (LN), neuropsychiatric lupus (NPLE) and neonatal lupus.
Untreated lupus can be fatal as it progresses from attack of skin and joints to internal organs, including lung, heart, and kidneys (with renal disease being the primary concern), thus making early and accurate diagnosis of and/or assessment of risk of developing lupus particularly critical. Lupus mainly appears as a series of flare-ups, with intervening periods of little or no disease manifestation. Kidney damage, measured by the amount of protein in the urine (proteinuria), is one of the most acute areas of damage associated with pathogenicity in SLE, and accounts for at least 50% of the mortality and morbidity of the disease, without any treatment.
Clinically, SLE is a heterogeneous disorder characterized by high-affinity autoantibodies (autoAbs). AutoAbs play an important role in the pathogenesis of SLE, and the diverse clinical manifestations of the disease are due to the deposition of antibody-containing immune complexes in blood vessels leading to inflammation in the kidney, brain and skin. AutoAbs also have direct pathogenic effects contributing to hemolytic anemia and thrombocytopenia. SLE is associated with the production of antinuclear antibodies, circulating immune complexes, and defect of the complement system. SLE has an incidence of about 1 in 700 women between the ages of 20 and 60, in black population. SLE can affect any organ system and can cause severe tissue damage. Numerous autoAbs of differing specificity are present in SLE. SLE patients often produce autoAbs having anti-DNA, anti-Ro, and anti-platelet specificity and that are capable of initiating clinical features of the disease, such as glomerulonephritis, arthritis, serositis, complete heart block in newborns, and hematologic abnormalities. These autoAbs are also possibly related to central nervous system disturbances. Arbuckle et al. described the development of autoAbs before the clinical onset of SLE (Arbuckle et al. N. Engl. J. Med. 349(16): 1526-1533 (2003)).
AutoAbs recognizing RNA-binding proteins (RBPs; also referred to as extractable nuclear antigens) were first characterized in SLE over 40 years ago (Holman, Ann N Y Acad. Sci. 124(2):800-6 (1965)). Such RBPs comprise a group of proteins—SSA (Ro52/TRIM21 and Ro60/TROVE2), SSB (La), U1 small nuclear ribonucleoprotein (RNP) protein and Smith (Sm) protein—with roles in RNA processing and biochemistry. Anti-SSA—and anti-SSB IgG autoAbs are found not only in SLE, but also Sjögren's and rheumatoid arthritis syndrome. Anti-SSA autoAbs are associated with subacute cutaneous lupus erythematosus, and with congenital heart block and neonatal lupus in children of anti-SSA positive women. Anti-SSB autoAbs are nearly always found together with anti-SSA autoAbs, and both autoantigens associate with cytoplasmic hYRNA (Lerner et al., Science 211(4480):400-2 (1981)). Anti-Sm autoAbs are highly specific for SLE and are generally found together with anti-RNP autoAbs. Both Sm and RNP proteins associate with specific snRNA species in the nuclear RNA spliceosome (Lerner et al., Proc Natl Acad Sci USA 76(11):5495-9 (1979)). Anti-RNP autoAbs are also found in patients with mixed connective tissue disease. It has been suggested that the presence of anti-RBP autoAbs may identify SLE cases that show less durable responses following B cell depletion therapy (Cambridge et al., Ann Rheum Dis 67:1011-16 (2008)).
Prior art discloses medicines for the treatment of autoimmune diseases. For instance, both international applications WO 03/020747 and WO 03/025014 disclose a fragment of snRNP 70 kDa, which is modified by phosphorylation and/or by acetylation, for treating such pathologies, i.e. autoimmune disease. However, further experimentation has indicated that the peptides disclosed in WO 03/020747 and WO 03/025014 are relatively unstable and rapidly eliminated when administered to mammals. Moreover, some of the disclosed peptides are inactive.
Therefore, there is a need to provide a better treatment for auto-immune pathologies.